Parenteral composition of paracetamol

ABSTRACT

The present invention refers to a pharmaceutical preparation, comprising a novel, stable solution of Paracetamol for parenteral administration, useful to establish an analgesic and antipyretic effect.

The present invention refers to pharmaceutical composition comprisingParacetamol for parenteral administration.

Paracetamol is considered to be the main active metabolite of phenacetinand acetanidile having analgesic and antipyretic properties. Paracetamolhas equivalent analgesic and antipyretic action to that of aspirinwhilst it expresses weak anti-inflammatory action therefore its use ininflammatory rheumatic diseases is limited.

The mechanism of its analgesic action is still unclarified. It isbelieved that it mainly acts by inhibiting prostaglandins biosynthesisand to a lesser extent by peripherically inhibiting algogenic stimulusorigin. The peripheral action is due also to inhibition of proglandinsbiosynthesis or to inhibition or to other endogenous substances actionthat sensitize pain's receptors after mechanic or chemical stimulation.

As far as its antipyretic action is concerned, Paracetamol inducestemperature fall to feverish but not to normal subjects.

It is believed that the antipyretic effect of Paracetamol is due tocentral action on the temperature controlled centre of hypothalamusresulting in peripheral vasodilation leading to skin peripheral bloodflow increase, perspiration and temperature loss.

This peripheral action of Paracetamol is due also to prostaglandinsbio-synthesis inhibition into hypothalamus. Paracetamol administered inrecommended dosage does not exert any effect of the cardiovascular andrespiratory system nor provokes acid-base balance disorders.

Several studies have confirmed the effectiveness and safety ofParacetamol's parenteral administration.

Paracetamol is well absorbed when intramuscularly administered and itsblood level is similar to that obtained after its oral administration.

The absorption rate is slower of that obtained when Paracetamol isorally administered, resulting in desirable blood levels for moreprolonged time.

There is also another advantage of injectable Paracetamol since the 20%loss of the drug that is observed after oral administration doesn'texist (Macheras et al. 1989, Pharmaceutical Codex 1994).

Paracetamol is metabolized by the microsomal enzymes of the liver and95% of it is excreted through urines as conjugated derivatives ofsulfuric (35%) and glucouronic acids (60%) whilst only 2% is excretedunchangeable (Gillette 1981, Clissold 1986, Remington 1990, Insel 1992,AMA-DE 1994).

Also a small part of Paracetamol, approx. 3%, is oxidized by the livercytochrome P-450 to a toxic intermediate metabolite that is connected tothe liver deposit of glutathione, producing finally a non-toxiccombination, which is excreted conjugated with cysteine and mercapturicacid (Mitchell et al. 1982, Jackson et at. 1984, Remington 1990, Insel1992).

Therefore, Paracetamol parenteral solutions are indispensable for use inmodern therapeutics for a greater and quicker therapeutic effect.

Whilst Paracetamol is soluble in many organic solvents, howeversolutions of Paracetamol with such solvents are unfit for therapeuticaluse, because of the produced toxicity when parenterally administered(intramuscularly or intravenously) and because of the present technicalproblems as i.e. chemical instability leading to precipitates, lowfluidity etc.

As above, the preparations of injectable solutions of Paracetamol andcombinations of Paracetamol with other active substances require thechoice of the suitable solvent or combination of solvents, comprisingalso water, reciprocating to certain requirements of suitability as: tobe pharmacologically inactive, to not form complexes with the activesubstance, to be blood conventional, free of sensitization or irritatingactivity, chemically stable, clear and not influenced by pHdeclinations.

Additionally, it is important the selected solvents to not interferewith Paracetamols' or other's substances therapeutical properties. Fromthe pharmacotechnical point of view, the selected solvent or solventssystem must have the full ability of mixing with water not only becausethis way it or they will facilitate the manufacturing process but willalso reduce the manufacturing cost.

Furthermore, the absorption by the organism of the solution and thecompatibility with the human blood are of high importance. Moreover,chemical stability is highly related to the antioxidant properties ofthe injectable solution.

Documents GR-B-871 510, GR-B-1 001 523, GR-B-1 002 731 and EPapplication number 97 600 009 are related to injectable parenteralsolutions including Paracetamol dissolved in Ethanol, Glycerol formaland Water. However, none of the said prior art documents combines boththe presence of Nipagin A and Nipasol M as antioxidant together withParacetamol as the only pharmaceutically active as in the presentinvention, as defined by the appended claims, in particular independentclaim 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is defined by the appended claims.

The claimed solutions overcome all the above problems of the prior art,i.e. they are chemically stable, clear, non-toxic, do not participate,show high fluidity, do not form complexes, are blood conventional, freeof sensitization or irritating activity, are not influenced by pHdeclinations, are well absorbed by the organism of human beings, arevery well compatible with the human blood, resist oxidation better thanall previous similar solutions in particular those comprising furtherpharmaceutical actives, are easy to produce, the organic solvents arefully mixing with water, show improved pharmacokinetic properties, showimproved bio-availability and local tolerance in the site of injection.

Since Paracetamol is practically insoluble in water, efforts made forits dissolution into organic-solvents or mixtures of them, suitable forparenteral use.

Paracetamol is soluble in Methanol, Ethanol, DMF, Ethylene chlorine,Benzyl ethanol and other organic solvents, but none of them can be usedalone or in a mixture, because of their toxicity. Our experiments showedfinally that the qualified solvent in the case of Paracetamol wasGlycerol formal.

Glycerol formal is an almost atoxic solvent (LD50 I.V. to rats, 3.5mg/kg body weight) possesses the advantage of mixing with Water, Alcoholand Propylene Glycol and has been proved to be the most favourable andqualified solvent for Paracetamol's injectable parenteral solutions,which can be used alone or in mixtures with water, Ethanol, Benzylethanol and Propylene glycol.

Further Compounds

One or more further additive compounds can also be included in theinvented composition.

Such additives can be Lidocaine HCl, pharmaceutical active showing theadvantage to attenuate pain at the site of injection, DisodiumPhosphate, Sodium hydroxide, Sodium carbonate or Disodium Citrate toadjust pH to 5-6.5, preferably to 5.5-6 even more preferably to 5.5,Disodium Edetate as chelating agent, Nipagin A and Nipasol M asantioxidant and other adjusting to the constituents antioxidant agents.

EXAMPLES

The following examples are according to the present invention as definedby independent claim 1 and show all the above nentioned advantages.

The advantages include improved antioxidant properties and absorptionproperties when compared either with the same solution but without theantioxidant mixture Nipagin A and Nipasol M or when said antioxidantmixture is fully or partially replaced by an other antioxidant such asSodium metabisulfite, derivatives of Ascorbic acid, derivatives carriersof Thiol group and/or Butyl Hydroxy Anisol or when compared with thesame solution including further pharmaceutical actives additionally toParacetamol such as the spasmolytic Hyoscine-N-Butylbromide the centralantalgic Codeine Phosphate or any synthetic or semi-synthetic morphinicanalgesic, the myorelaxants Carisoprodol and Orphenadrine citrate, theanti-oxidant Acetyl-cysteine, the analgesic Acetylsalicylic acid,Caffeine and pharmaceutically accepted combinations of them withParacetamol.

Example 1

Constituents Quantities Paracetamol 150.00 mg Lidocaine HCl 5.00 mgDisodium Edetate 0.50 mg Disodium Phosphate q.s. to pH 5-5.5 Nipagin A1.80 mg Nipasol M 0.20 mg Glycerol formal 0.75 ml Ethanol 0.15 ml Waterfor injection q.s. to 1.00 ml

Example 2

Constituents Quantities Paracetamol 150.00 mg Lidocaine HCl 5.00 mgDisodium Edetate 0.50 mg Disodium Phosphate q.s. to pH 5-5.5 ButylHydroxy Anisol 0.20 mg Ascorbic acid 0.50 mg Glycerol formal 0.75 mlEthanol 0.15 ml Water for injection q.s. to 1.00 ml

Example 3

Constituents Quantities Paracetamol 150.00 mg Lidocaine HCl 5.00 mgDisodium Edetate 0.50 mg Disodium Phosphate q.s. to pH 5-5.5 Sodiummetabilulfite 1.00 mg Glycerol formal 0.75 ml Ethanol 0.15 ml Water forinjection q.s. to 1.00 ml

Example 4

Constituents Quantities Paracetamol 150.00 mg Lidocaine HCl 5.00 mgDisodium Edetate 0.50 mg Disodium Phosphate q.s. to pH 5-5.5 Nipagin A1.80 mg Nipasol M 0.20 mg Glycerol formal 0.70 ml Propylene glycol 0.20ml Water for injection q.s. to 1.00 ml

Example 5

Constituents Quantities Paracetamol 150.00 mg Hyoscine-N-Butylbromide5.00 mg Lidocaine HCl 5.00 mg Disodium Edetate 0.50 mg Sodium hydroxideq.s. to pH 5-5.5 Nipagin A 1.80 mg Nipasol M 0.20 mg Glycerol formal0.75 ml Ethanol 0.15 ml Water for injection q.s. to 1.00 ml

Example 6

Constituents Quantities Paracetamol 120.00 mg Codeine Phosphate assulphate 6.50 mg Lidocaine HCl 5.00 mg Disodium Edetate 0.50 mg DisodiumPhosphate q.s. to pH 5-5.5 Butyl Hydroxide Anisol 0.20 mg Ascorbic acid0.50 mg Glycerol formal 0.75 ml Propylene glycol 0.20 ml Water forinjection q.s. to 1.00 ml

Example 7

Constituents Quantities Paracetamol 100.00 mg Carisoprodol 50.00 mgLidocaine HCl 5.00 mg Disodium Edetate 0.50 mg Sodium hydroxide q.s. topH 5-5.5 Nipagin A 1.80 mg Nipasol M 0.20 mg Glycerol formal 0.75 mlEthanol 0.15 ml Water for injection q.s. to 1.00 ml

Example 8

Constituents Quantities Paracetamol 60.00 mg Acetylsalicylic acid 100.00mg Caffeine 10.00 mg Lidocaine HCl 5.00 mg Sodium hydroxide q.s. to pH5-5.5 Disodium Edetate 0.50 mg Nipagin A 1.80 mg Nipasol M 0.20 mgAscorbic acid 0.50 mg Glycerol formal 0.80 ml Propylene glycol 0.10 mlWater for injection q.s. to 1.00 ml

1. Pharmaceutical injectable parenteral solution comprising a)Paracetamol as the only pharmaceutically active, b) a mixture ofsolvents comprising Ethanol, Glycerol formal and Water and c) theantioxidant mixture Nipagin A (is the Trade Name of CLARIANT UK LTDcompany and corresponds to Methyl-parahydroxy benzoate) and Nipasol M(is the Trade Name of CLARIANT UK LTD company and corresponds toPropyl-parahydroxy benzoate).
 2. Solution according to claim 1 whereinthe ratio ethanol:glycerol formal:water is 5-15:60-80:5-10 by volume. 3.Solution according to claim 1 or 2 containing one or more antioxidantagents such as Sodium metabisulphite, derivatives of Ascorbic acid,derivatives carriers of Thiol group or Butyl Hydroxide Anisol. 4.Solution according to claim 1 or 2 containing one or more of Sodiumhydroxide, Sodium carbonate, Trisodium citrate, Disodium phosphate toachieve a pH of 5-6.5.
 5. Solution according to claim 1 or 2 containingDisodium edetate.
 6. Solution according to claim 1 or 2 containingBenzyl alcohol or Propylene glycol.
 7. Solution according to claim 1 or2 containing one or more pharmaceutical actives such asHyoscine-N-Butylbromide, Codeine phosphate or Sulfate, Carisoprodol,Orphenadrine citrate, Acetylsalicylic acid, Caffeine, synthetic orhemi-synthetic morphinic derivatives.
 8. Solution according to claim 1comprising 150 mg Paracetamol, 5 mg Lidocaine HCl, 0.40 mg Disodiumphosphate, 0.50 mg Disodium Edetate, 1.8 mg Nipagin A, 0.20 mg NipasolM, 0.75 ml Glycerol formal, 0.15 ml Ethanol and Water for injection q,s.ad 1 ml.
 9. Solution according to claim 1 wherein the ratio Glycerolformal-Propylene glycol-Water is 60-80:20-40:5-15 by volume. 10.Solution according to claim 1 wherein the ratio Glycerol formal-Benzylalcohol-Water is 80:10:10 by volume.
 11. Pharmaceutical injectableparenteral solution comprising a) Paracetamol as the onlypharmaceutically active, b) a mixture of solvents comprising Ethanol,Glycerol formal and Water and c) the antioxidant mixture Nipagin A (isthe Trade Name of CLARIANT UK LTD company and corresponds toMethyl-parahydroxy benzoate) and Nipasol M (is the Trade Name ofCLARIANT UK LTD company and corresponds to Propyl-parahydroxy benzoate),wherein the ratio ethanol: glycerol formal:water is 5-15:60-80:5-10 byvolume.
 12. Solution according to claim 11 containing one or moreantioxidant agents such as Sodium metabisulphite, derivatives ofAscorbic acid, derivatives carriers of Thiol group or Butyl HydroxideAnisol.
 13. Solution according to claim 11 or 12 comprising containingone or more of Sodium hydroxide, Sodium carbonate, Trisodium citrate,Disodium phosphate to achieve a pH of 5-6.5.
 14. Solution according toclaim 11 or 12 containing Disodium edetate.
 15. Solution according toclaim 11 or 12 comprising containing Benzyl alcohol or Propylene glycol.16. Solution according to claim 11 or 12 containing one or morepharmaceutical actives such as Hyoscine-N-Butylbromide, Codeinephosphate or Sulfate, Carisoprodol, Orphenadrine citrate,Acetylsalicylic acid, Caffeine, synthetic or hemi-synthetic morphinicderivatives.
 17. Pharmaceutical injectable parenteral solutioncomprising 150 mg Paracetamol, 5 mg Lidocaine HCl, 0.40 mg Disodiumphosphate, 0.50 mg Disodium Edetate, 1.8 mg Nipagin A (is the Trade Nameof CLARIANT UK LTD company and corresponds to Methyl-parahydroxybenzoate), 0.20 mg Nipasol (is the Trade Name of CLARIANT UK LTD companyand corresponds to Propyl-parahydroxy benzoate), 0.75 ml Glycerolformal, 0.15 ml Ethanol and Water for injection q.s. ad 1 ml. 18.Pharmaceutical injectable parenteral solution comprising a) Paracetamolas the only pharmaceutically active, b) a mixture of solvents comprisingEthanol, Glycerol formal and Water and c) the antioxidant mixtureNipagin A (is the Trade Name of CLARIANT UK LTD company and correspondsto Methyl-parahydroxy benzoate) and Nipasol M (is the Trade Name ofCLARIANT UK LTD company and corresponds to Propyl-parahydroxy benzoate),wherein the ratio Glycerol formal-Propylene glycol-Water is60-80:20-40:5-15 by volume.
 19. Pharmaceutical injectable parenteralsolution comprising a) Paracetamol as the only pharmaceutically active,b) a mixture of solvents comprising Ethanol, Glycerol formal and Waterand c) the antioxidant mixture Nipagin A (is the Trade Name of CLARIANTUK LTD company and corresponds to Methyl-parahydroxy benzoate) andNipasol M (is the Trade Name of CLARIANT UK LTD company and correspondsto Propyl-parahydroxy benzoate), wherein the ratio Glycerolformal-Benzyl alcohol-Water is 80:10:10 by volume.
 20. Pharmaceuticalinjectable parenteral solution comprising a) Paracetamol as the onlypharmaceutically active or in combination with further compoundscomprising one or more pharmaceutical actives such asHyoscine-N-Butylbromide, Codeine phosphate or Sulfate, Carisoprodol,Orphenadrine citrate, Acetylsalicylic acid, Caffeine, synthetic orhemi-synthetic morphinic derivatives, b) a mixture of solventscomprising Ethanol, Glycerol formal and Water and c) the antioxidantmixture Nipagin A and Nipasol M wherein the ratio Glycerolformal-Propylene glycol-Water is 60-80:20-40:5-15 by volume. 21.Pharmaceutical injectable parenteral solution comprising a) Paracetamolas the only pharmaceutically activeor in combination with furthercompounds comprising one or more pharmaceutical actives such asHyoscine-N-Butylbromide, Codeine phosphate or Sulfate, Carisoprodol,Orphenadrine citrate, Acetylsalicylic acid, Caffeine, synthetic orhemi-synthetic morphinic derivatives, b) a mixture of solventscomprising Ethanol, Glycerol formal and Water and c) the antioxidantmixture Nipagin A (is the Trade Name of CLARIANT UK LTD company andcorresponds to Methyl-parahydroxy benzoate) and Nipasol M (is the TradeName of CLARIANT UK LTD company and corresponds to Propyl-parahydroxybenzoate), wherein the ratio Glycerol formal-Benzyl alcohol-Water is80:10:10 by volume.
 22. Solution according to claim 2, wherein the ratiois 15:75:10 by volume.
 23. Solution according to claim 4, wherein the pHis 5.5-5.6.
 24. Solution according to claim 9, where the ratio is70:20:10 by volume.
 25. Solution according to claim 13, wherein the pHis 5.5-5.6.